Abstract
Estimates from large scale genome sequencing studies indicate that each human carries up to 20 genetic variants that are predicted to results in loss of function (LOF) of protein-coding genes. While some are known disease-causing variants or common, tolerated, LOFs in non-essential genes, the majority remain of unknown consequence. We explore the possibility of using imputed GWAS data from large biorepositories such as the electronic medical record and genomics (eMERGE) consortium to determine the effects of rare LOFs. Here, we show that two hypocholesterolemia-associated LOF mutations in the PCSK9 gene can be accurately imputed into large-scale GWAS datasets which raises the possibility of assessing LOFs through genomics-linked medical records.
Highlights
Complete loss of function (LOF) variants are defined as variants expected to correlate with complete LOF of affected transcripts; i.e., nonsense mutations, splice site mutations, and insertion/deletion variants that result in downstream premature stop codons, or larger deletions removing either the first exon or more than 50% of the protein-coding sequence of the affected transcript (MacArthur et al, 2012)
MATERIALS AND METHODS The Center for Applied Genomics (CAG) at The Children’s Hospital of Philadelphia (CHOP) maintains a biorepository of over 160,000 genotyped samples, 60,000 of which are pediatric samples randomly recruited from CHOP with complete electronic medical records (EMR)
We have shown a successful proof of concept that rare LOFs can be imputed into high density genotyping array data using data from large scale sequencing projects such as the 1KGP as a reference
Summary
Complete loss of function (LOF) variants are defined as variants expected to correlate with complete LOF of affected transcripts; i.e., nonsense mutations, splice site mutations, and insertion/deletion (indel) variants that result in downstream premature stop codons, or larger deletions removing either the first exon or more than 50% of the protein-coding sequence of the affected transcript (MacArthur et al, 2012). Genes containing common LOFs are strongly enriched for functional categories related to olfactory reception that are apparently unessential and do not result in any severe medical consequence. Common LOFs are enriched at the 3 ends of genes as these mutations escape nonsense-mediated decay and are less subject to purifying natural selection. The population frequency of individual LOFs would appear to correlate with their potential to adversely affect human health
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
